Review

One year in review: novelties in the treatment of G.M. Guidelli1, T. Barskova2, M.G. Brizi1, G. Lepri2, A. Parma3, R. Talarico3, L. Cantarini1, B. Frediani1

1Department of Rheumatology, Policlinico ABSTRACT ty of the scientific effort was addressed Le Scotte, University of Siena, Siena, Italy; Rheumatoid arthritis (RA) is a chronic to these new drugs. Nevertheless, the 2 Rheumatology Unit, Department of disease characterised by inflammation “old” DMARDs still represent a basic Experimental and Clinical Medicine, of the synovial tissue in joints, which approach for RA patients, according to Azienda Ospedaliero-Universitaria Careggi, University of Florence, can lead to joint destruction. The prima- the 2010 EULAR recommendations Florence, Italy; ry aim of the treatment is to control pain (6). MTX is one of the DMARDs and 3Rheumatology Unit, Department of and inflammation, reduce joint damage is the most commonly used agent for Clinical and Experimental Medicine, and disability, and maintain or improve treating RA. When MTX monothera- University of Pisa, Pisa, Italy. physical function and quality of life. In py provides inadequate disease con- Giacomo M. Guidelli, MD this article, we provide a critical analy- trol, combination therapies with other Tatiana Barskova, MD sis of the recent literature on the novel- DMARDs, such as biological agents, M. Giuseppina Brizi, MD ties in the treatment of RA, with a partic- is selected. Although the distinct ef- Gemma Lepri, MD ular focus on the most relevant studies ficacy of MTX with biological agents Alice Parma, MD Rosaria Talarico, MD, PhD published over the last two years. has been reported, some patients dis- Luca Cantarini, MD, PhD continue the biological agents because Bruno Frediani, Professor Introduction of adverse events, or inadequate or Please address correspondence to: Rheumatoid arthritis (RA) is a chronic non-response. Therefore, the identifi- Dr Luca Cantarini, autoimmune disease characterised by cation of other effective DMARDs for Research Centre of Systemic Autoimmune inflammation and deterioration of the combination treatment with MTX is and Autoinflammatory Diseases, joints, which can produce a loss of important. Although it is not a first-line Policlinico Le Scotte, functionality, reduces quality of life DMARD, tacrolimus (TAC) is an ef- University of Siena, Viale Bracci 1, and enhances morbidity and mortality. fective alternative. TAC is an oral cal- 53100 Siena, Italy. The objective of treatment is to achieve cineurin inhibitor (CNI) that has been E-mail: [email protected] complete remission. Current treatment approved to prevent allograft rejection Received on February 20, 2015; models promote intensively treating in- after liver and kidney transplantation. accepted on February 23, 2015. flammation early in the disease course It suppresses the proliferation and ac- Clin Exp Rheumatol 2015; 33: 102-108. and it is recommended to start with dis- tivation of antigen-specific T cells. © Copyright Clinical and ease-modifying anti-rheumatic drugs Because T cells play an important role Experimental Rheumatology 2015. (DMARDs) as soon as the diagnostic in the pathogenesis of RA, TAC was has been established. In general, treat- applied as a treatment option for RA, Key words: rheumatoid arthritis, ment begins with methotrexate (MTX). especially in Japan and the USA. Re- treatment, novelties However, in patients with high RA ac- cently, the efficacy of TAC in RA was tivity, in which a rapid progression can assessed in three different studies; Ki- be expected, a combination of MTX tahama et al. (7) demonstrated the ef- and a biologic agent is used. In this one ficacy of add-on therapy with TAC to year review we reviewed articles pub- MTX in a group of 175 RA patients, lished during 2013 and 2014 and select- compared to 471 controls (MTX alone ed articles focusing on the novelties in or plus another one DMARD), show- the treatment of RA. ing a significant decrease in the DAS28 score. Tanaka et al. (8) showed, in their DMARDs multicentre RCT how adding TAC to Since 1999, the introduction of the first MTX in 61 patients resulted in a sig- biologic agents represents a “turning nificant suppression of disease activity point” in the treatment of RA (1-5). On and joint destruction, evaluated by the Competing interests: none declared. this basis, it is evident how the majori- change in the total Sharp score. Simi-

102 Novelties in the treatment of RA / G. Guidelli et al. REVIEW larly, Kanzaki et al. (9) retrospectively oid administration (14). However, ac- Anti--6 (IL-6) family analyzed the clinical course of 24 RA cording to the Care-RA trial conducted Cytokines have a major role in causing patients treated with a combination of on 290 DMARD naïve-patients with joint damage. IL-6 is a pleiotropic cy- MTX and TAC; after 3 years of treat- early RA at high risk of disease pro- tokine with diverse activities and plays ment the DAS28 was decreased from gression, MTX plus a moderate dose a central role in the pathogenesis of RA 4.81 to 3.41, glucocorticoids doses de- of prednisone (30 mg daily) proved to by contributing to T cell activation, B creased from 5.1 to 3.2 and 19/24 pa- be as effective as DMARD combina- cell activation, synoviocyte stimula- tients were still treated with the same tion therapies (MTX+Sulfasalazine or tion, endothelial activation, osteoclast combination-regimen. Other than the MTX+Leflunomide) associated with maturation and production of acute- control of the clinical manifestations moderate or high prednisone dosages phase proteins (19). Serum levels of of the disease, in 2013 Kang et al. (10) (up to 60 mg/daily) in inducing disease IL-6 and soluble IL-6 receptor (IL-6R) showed the potential benefit of TAC remission at 16-week follow-up (15). are elevated and correlate with disease on bone metabolism; indeed, 28 RA Recently, growing interest has been activity in RA patients and so blocking patients in three centres received TAC arisen on the evaluation of oral versus IL-6/IL-6R has been considered benefi- 3 mg once daily for 24 weeks and this subcutaneous MTX administration. In cial for the treatment of RA. In accord- treatment increased bone formation particular, the retrospective MENTOR ance with this, accumulated evidence marker such as osteocalcin while C-tel- study conducted by Scott et al. on 196 has shown the clinical efficacy as well opeptide of type I collagen (sCTx-I) did RA patients, showed that subcutaneous as the adequate safety of , not change its serum concentrations. MTX was more effective than oral for- a humanised anti-IL-6R monoclonal Glucocorticoids (GC) are fast-acting mulation when used at the same dosage antibody (mAb), as monotherapy or anti-inflammatory drugs, now also con- (16). In addition, a better bioavailabil- in combination with synthetic disease- sidered as disease-modifying because ity and a lower incidence of gastro-in- modifying anti-rheumatic drugs (sD- of their ability to decelerate structural testinal side effects were identified in MARDs) such as methotrexate (MTX) damage (11). Especially during the first patients administered with subcutane- in patients who are sDMARD naive and weeks of DMARD treatment, GC are ous MTX. Iguratimod (T-614) is a nov- have an inadequate response to tumour frequently used due to the rapid onset el anti-rheumatic drug that suppresses necrosis factor (TNF) inhibitors.(20) of their anti-inflammatory efficacy. In IL-6, IL-8 and monocyte chemoattract- Also, in the 2013 EULAR recommen- 2014 Den Uyl et al. (12) demonstrated ant protein 1 production induced by dations for the management of RA, to- how the COBRA-light therapy (pred- tumour necrosis factor-α via the inhi- cilizumab was listed as a first-line TNF nisone 30 mg/daily, tapered to 7.5 mg bition of nuclear factor-kappa B acti- inhibitor in patients with sDMARD-IR /daily in 9 weeks, plus MTX 10 mg/ vation (17). Also, Iguratimod reduces (21). The successful treatment of RA weekly) is not inferior to COBRA strat- immunoglobulin production by act- by tocilizumab has encouraged the de- egy (with a 60 mg/daily of prednisone ing directly on human B lymphocytes velopment of novel biologic DMARDs starting dose). Disease activity rapidly without affecting B lymphocyte prolif- (bDMARDs) targeting IL-6 or IL-6R. decreased in both groups, and not sig- eration and significantly decrease the In addition to tocilizumab, the phase II nificant difference were found for func- production of rheumatoid factor, IgG, clinical trials of , tional ability and CRP levels. Among IgM and IgA. For this reason, given and , three new bDMARDs GCs, methylprednisolone (MP) is the the peculiar mechanism of action, igu- targeting IL-6 are reported. All these standard steroid for the pulse therapy, ratimod has been suggested as a further drugs were studied in RA patients with but Sadra et al. (13) recently showed DMARD for RA patients. A recent moderate-to-severe disease activity de- how dexamethasone (DEX) (longer randomised, double-blind, placebo spite TNF inhibitors. half-life, higher anti-inflammatory ac- controlled trial conducted by Ishiguro tivity and munch cheaper than MP) et al. and a subsequent open-label ex- Olokizumab is safe and effective treatment for se- tension study (18) disclosed that the Olokizumab is a humanised anti-IL-6 vere RA flares. The authors described combination Iguratimod/MTX therapy mAb targets the IL-6 cytokine rather the clinical improvement (by DAS28 proved to be effective in achieving a than the receptor. Genovese et al. (22) score) of 14 RA patients, treated with low disease activity (ACR 20, 50, 70 report the findings of a 12-week phase 3 consecutive days of 120 mg DEX, and DAS28-CRP) and an improved IIb study to assess the safety and effi- compared to 16 patients treated with 1g quality of life. Moreover, the combina- cacy of subcutaneous olokozumab in of MP, for the same period. With regard tion therapy was well tolerated and a patients with rheumatoid arthritis (RA) to MTX, the tREACH trial conducted good safety profile was highlighted. As with moderate-to -severe disease activ- on 281 RA patients in order to compare a consequence, the authors suggested ity who had previously failed tumour efficacy of initial triple DMARD ther- that Iguratimod+MTX may represent a necrosis factor (TNF) inhibitor therapy. apy with MTX as monotherapy, found good treatment option for patients with Patients were randomised to one of that the DMARD combination group inadequate response to MTX alone or nine treatment arms receiving placebo showed better results than the MTX non eligible for other DMARDs or bio- or olokizumab 60, 120 or 240 mg every alone group, regardless of corticoster- logical agents. 4 weeks (q4w) or every 2 weeks (q2w),

103 REVIEW Novelties in the treatment of RA / G. Guidelli et al. or 8 mg/kg tocilizumab q4w. Oloki- placebo (26.7% vs. 3.3%). Greater im- who had inadequate responses to pre- zumab at various doses across multiple provements in mean DAS28-CRP at vious tumour necrosis factor blocker endpoints demonstrated significantly week 12 were observed with siruku- therapy. greater reductions in DAS28 (CRP) and mab 100 mg q2w versus placebo. The most higher ACR20 e ACR50 respons- incidence of adverse events was simi- es compared with placebo and similar lar for sirukumab-treated and placebo- Secukinumab is a fully human immuno- efficacy to tocilizumab. Most adverse treated patients. Infections were the globulin (Ig)-G1κ events were mild or moderate and com- most common type of adverse events; that binds with high affinity and selec- parable between olokizumab and tocili- one death occurred (Part B, sirukumab tivity to human IL-17A, resulting in the zumab treatment groups. 100 mg q2w, brain aneurysm). Safety neutralisation of the cytokine activity results through 38 weeks were consist- Recently, Genovese et al. (25) report- Sarilumab ent with other IL-6 inhibitors. ed results of II phase long-term study Sarilumab is a fully human anti-inter- Soon all these bDMARDs will be avail- (52-week) evaluation of safety and ef- leukin 6 receptor α (anti-IL-6Rα) mon- able for targeting IL-6, which will raise ficacy of secukinumab in RA patients oclonal antibody. Huizinga et al. (23) questions as to when and how these with inadequate response to sDMARDs reported the results of a 12-week phase agents should be used. Indeed, all these or bDMARDs. All patients received II study, aimed at assessing the safety studies demonstrated clinical efficacy monthly subcutaneous injections of and efficacy of subcutaneous sarilumab. as well as safety profiles appear similar secukinumab (25, 75, 150, or 300 mg), All enrolled patients with active RA de- among tocilizumab, olokizumab, sari- or placebo. In patients taking 150 mg spite MTX were randomised to one of lumab and sirukumab, making it diffi- of secukinumab, responses were im- six treatment arms receiving placebo or cult to differentiate between them com- proved through Week 52 (ACR50: sarilumab (100 mg q2w, 150 mg q2w, pared to tocilizumab. Further studies Week 16=45%, Week 52=55%; 100 mg qw, 200 mg q2w or 150 mg qw are warranted to establish whether there DAS28-CRP ≤2.6: Week 16=25%, for 12 weeks) with background MTX. are important differences among the Week 52=40%). The rate of adverse The proportion of patients achieving the five IL-6 inhibitors, and to determine events (AE) from weeks 20 to 60 was primary endpoint, an ACR20 response which inhibitor should be chosen for a 64.8%, with most AE being mild to at week 12, compared to placebo was particular patient from a clinical stand- moderate in severity. The overall rate significantly higher for sarilumab 150 point as regards clinical response and/ of infections was 31.9%, most being mg qw e 150 mg q2w versus placebo. or structural damage, adverse events, mild (predominantly nasopharyngitis). Sarilumab was generally well tolerated and efficacy in patients with inadequate Serious AE were reported in 21 patients and infections were the most common response to TNF. (8.9%). There were 3 reports of malig- adverse events, although no serious nancies (ovarian, lung, basal cell), and infections were reported. At week 12, Targeting interleukin-17 (IL-17) no deaths between weeks 20 and 60. mean total cholesterol was higher in the in active RA Strand et al. (26) presented study of RA four highest dose groups compared to Clinical and experimental evidence patients with incomplete responses to placebo group. suggest that interleukin-17A (IL-17A; methotrexate were randomised equally also known as IL-17) is an attractive to receive monthly subcutaneous injec- Sirukumab therapeutic target in rheumatoid arthri- tions of secukinumab 25 mg, 75 mg, Sirukumab is a human anti-IL-6 mAb. tis (RA). Rheumatoid synovial tissue 150 mg, 300 mg or placebo. Clinical Smolen et al. (24) report the findings of produces IL-17A, which causes carti- endpoints used in this study included two parts of a phase II study to assess lage and bone degradation in synovial the ACR response criteria and its com- the safety and efficacy of subcutane- and bone explants. Serum IL-17A lev- ponents and simplified disease activity ous sirukumab in patients with active els and, to a greater extent, synovial flu- score. Patients who achieved ACR20 RA despite MTX. In Part A (proof-of- id IL-17A levels are elevated in many responses on secukinumab had statis- concept), 36 patients were randomised patients with RA. In some RA cohorts, tically significant and clinically mean- to placebo or sirukumab 100 mg q2w higher IL-17A levels have been associ- ingful improvements in Health related through week 10, with crossover treat- ated with a more severe clinical course. quality of life (HRQoL), which were ment during weeks 12–22. In Part B Several IL-17A blockers, including the seen across patient-reported outcomes (dose finding), 151 patients were ran- anti- IL-17A monoclonal antibodies (PRO) included Health Assessment domised to sirukumab (100 mg q2w, secukinumab and , and the Questionnaire-Disability Index (HAQ- 100 mg q4w, 50 mg q4w, or 25 mg q4w) anti-IL-17 receptor subunit A mono- DI), Medical Outcomes Study Short through week 24, or placebo through clonal antibody have been Form-36 [SF-36] Survey, and Function- week 10 with crossover to sirukumab evaluated in phase II clinical trials. al Assessment of Chronic Illness Ther- 100 mg q2w (weeks 12–24). The pri- Of these, secukinumab is the most ad- apy-Fatigue (FACIT-Fatigue). Levels mary endpoint (ACR50 response at vanced with respect to clinical evalua- of ACR response were associated with week 12 in Part B) was achieved only tion in RA, with phase III trials ongoing incre­mentally greater HRQoL improve- with sirukumab 100 mg q2w versus in patients on background methotrexate ments. The REASSURE 1 trial (started

104 Novelties in the treatment of RA / G. Guidelli et al. REVIEW in 2011 and estimated study completion nificantly better with ixekizumab than for the treatment of RA patients, as it date at 2017) is comparing the safety placebo. Ixekizumab improved RA reduces the synthesis of autoreactive and efficacy of secukinumab 75 and signs and symptoms in patients of both antibodies as rheumatoid factor and 150 mg versus placebo when added to groups. The safety profile was similar anti-citrullinated peptide antibody, and background methotrexate therapy (7.5– to that of other biologic agents, with no modifies the antigen presentation to T 25 mg/week) in patients with a TNF-IR unexpected safety concerns. Adverse cells as well as cytokine production. and active RA. The primary efficacy events occurred with similar frequen- outcome is ACR20 rate at week 24, cies overall in the ixekizumab and and key secondary outcomes include placebo groups. Infections were more Ocrelizumab is another -deplet- changes from baseline in HAQ-DI, frequent with ixekizumab than placebo ing agent, it is a humanised anti-CD20 radiographic progression, and major (biologic-naive 25% vs. 19%; inad- monoclonal antibody and it seemed to clinical response rate (defined as 70% equate responders to TNF inhibitors be effective in RA treatment. Large improvement in ACR response over 6 27% vs. 25%). No mycobacterial or in- clinical trials have evaluated the OCR continuous months). Planned accrual is vasive fungal infections were reported. therapy in RA demonstrating a compa- 630 patients. Development of this agent is currently rable efficacy than RTX, with compara- The NURTURE 1 trial (started at 2011 focused on psoriasis and psoriatic ar- ble responder rates (31-33). These stud- end estimated study completion is thritis. ies have evaluated the efficacy of OCR 2015) is also comparing the safety and in patients with inadequate response to efficacy of secukinumab 75 and 150 Brodalumab MTX, in patients with an inadequate mg versus placebo in patients with a Brodalumab is a fully human IgG2 response to TNFi and in those naïve to TNF-IR and active RA [ClinicalTrials. anti-IL-17RA monoclonal antibody. MTX and biological therapy. In Febru- gov identifier: NCT01350804]. -How Martin et al. (28) presented phase Ib ary 2014 results from the Ocrelizumab ever, this study also includes a fourth study enrolled subjects with moderate (OCR) phase III programme have been arm with the active comparator abata- to severe. Subjects were randomised published (34) showing a comparable cept, and study treatments are being 3:1 to receive brodalumab (50 mg, 140 safety profile of OCR 200 mg x 2+MTX added to background therapy with sta- mg, or 210 mg subcutaneously every and placebo+MTX. In this study 868 ble doses of methotrexate (7.5–25 mg/ two weeks for 6 doses per group; or patients received placebo, 1064 OCR week) or another single conventional 420 mg or 700 mg intravenously every 400 mg (200 mg x 2 or 400 mg x 1) DMARD. The ACR20 rate at week 24 4 weeks for two doses per group or pla- (OCR200) and 827 OCR 500 mg x 2 is the primary efficacy outcome, and cebo. Multiple dose administration of (OCR500) plus background MTX at changes from baseline in HAQ-DI and brodalumab was tolerated in subjects baseline and 24 weeks. OCR500+MTX major clinical response rate are key with active RA. There was no evidence may be an effective therapeutic strat- secondary outcome measures. Planned of a clinical response to brodalumab in egy in RA treatment, as demonstrated accrual is 548 patients. subjects with RA. The study investiga- clinical benefit by improving RA signs tors concluded that there was no evi- and symptoms and radiographic out- Ixekizumab dence of meaningful clinical efficacy, comes (34-35). However, the study Ixekizumab is a humanised IgG4 anti- and therefore these preliminary results of Emery et al. demonstrated a dif- IL-17A monoclonal antibody was eval- are not supportive of further evaluation ference in the safety profile regard- uated in two studies. of this agent in RA. As for ixekizumab, ing severe infectious events between Previously Genovese et al. (2010) re- no trials in RA are ongoing and devel- OCR500+MTX and placebo+MTX. ported results of phase I study active opment is currently focused on psoria- This difference in safety profile was RA patients were intravenous ixeki- sis and psoriatic arthritis. not observed between placebo+MTX zumab added to DMARDs improved and OCR200+MTX, that, however, did signs and symptoms of RA, with no Therapies targeting B cells not show superior efficacy compared strong adverse safety. This first evalua- In addition to therapies selectively act- with existing therapies. No differences tion of ixekizumab supports neutraliza- ing on kay molecules in RA, also to in the rate of malignancies between tion of IL-17 as a potential novel goal target or to modulate circulating leu- treatment groups were reported by the for the treatment of RA. kocyte subsets and/or within the target OCR phase III programme. In more recent phase II trial (27), sub- tissues has been tested. In this setting, cutaneous ixekizumab or placebo was some studies have suggested changes Ofatumumab added to background DMARD therapy in B cell populations in patients with Ofatumumab is another B cell-depleting in two group of RA patients: biologics- RA (29-30), these data indicate that agent that requires premedication with naive and patients with an inadequate the targeting of B cells may be impor- corticosteroids in order to avoid reac- response to tumour necrosis factor tant in the treatment of patients with tions during infusions. It is a human- (TNF) inhibitors. For patients with an RA. The treatment with rituximab a ised monoclonal antibody that targets inadequate response to TNF inhibitors, chimeric mouse-human monoclonal extracellular domains of CD20 antigen. ACR20 responses at week 12 were sig- antibody anti-CD20 cells is approved Two trials have reported a comparable

105 REVIEW Novelties in the treatment of RA / G. Guidelli et al. efficacy of ofatumumab and RTX in RA dicated a significantly reduction of RA This seems to modulate intracellular demonstrating similar ACR responder signs and symptoms with a good safety signalling transduction, resulting in rates and relatively common infusion profile of the drug. In this trial the pri- differentiation and activation of lym- related adverse events (36-37). mary end point was the proportion of phocytes as well as in the release of In the review of Faurschou et al. it is patients reaching an ACR20 response at proinfiammatory cytochines (such as reported that neither ocrelizumab nor week 16 and “Tabalumab (doses of 30, tumour necrosis factor-TNF-α), that ofatumumab are licensed for clinical 60 and 160 mg) or placebo was admin- lead to joint inflammation and damage. use in patients with RA (38). istrated intravenously over 30 minutes Tofacitinib (Xeljanz – produced by The B-cell activating factor (BAFF) ex- at weeks o, 3 and 6” (29). MTX was Pfizer, development code CP-690,550, ists as a soluble form and a membrane- continued during the study, but none formerly named tasocitinib) is a small bound form playing an important role received other DMARDs or biological molecule that inhibits in order of po- in B cell generation and maintenance. It drugs and no more of 10 mg corticoster- tency JAK 3 over JAK1 and JAK 2 is a ligand in the TNF family requested oids daily. The primary end point was over Tyk2. It is an orally drug with a for B-cell survival (39). An alteration reached at week 16 and similar signifi- half life of about 3.5 hours. It is elimi- in B cell activation, proliferation, sur- cant differences in response rates were nated for 70% by hepatic metabolism vival and consequently immunoglobu- noted in the secondary end points as and for the remaining by renal excre- lin secretion may be caused by a BAFF ACR50, ACR70, DAS28 and EULAR tion. There are two doses of the drug: 5 dysregulation. For this reason acting on response. In addition, no differences in mg twice daily and 10 mg twice daily. BAFF in order to neutralise may be an the incidence of adverse events were In the last years, six Phase III studies alternative therapeutic choice in RA; in noted between patients treated with ta- have been developed to evaluate the ef- addition studies have showed an abnor- balumab and those treated with place- ficacy and safety of this drug in adult mal high concentration of BAFF in RA bo. The efficacy of tabalumab was also patients with moderate to severe RA. patients (40). studied in patients with active RA and All these studies are named under the an inadequate response to TNF inhibi- acronym ORAL (Oral Rheumatoid Ar- tors (39). For this study patients with thritis Phase III Trials): Belimumab is a monoclonal humanised RA from 45 centres were enrolled, all ORAL Solo (30), Sync (31), Standard antibody targeting soluble BAFF and patients had RA diagnosis defined by (32), Scan (33), Step (34) and Start (35). its use in RA was studied in a placebo- the American Rheumatism Association They were multicentre, double-blind, controlled trial with the enrolment of 1987 revised criteria and all had an his- placebo controlled, parallel group study 283 patients with a active RA despite tory of inadequate response or intoler- design trials. In these trials, patients therapy with DMARDs (38). A review ance to one or more TNFi. The primary were allowed to receive background summarised pharmacological and clini- end point was the percentage of patients therapies (NSAIDs – non-steroidal anti cal data on belimumab, a fully human reaching an ACR50 response at week inflammatory drugs, opioids or corticos- monoclonal antibody that acts neutral- 16 and it was not statistically differ- teroids). These trials showed significant ising soluble BAFF, in RA patients. ent between the combined Tabalumab improvement in RA as measured by However, this trial suggested a relative group and the placebo one. On the con- ACR scores increase by 20-50-70%, low efficacy of belimumab in RA pa- trary the ACR20 and ACR50 response disease remission scores, self-reported tients. Therapy with belimumab seems percentage was significantly greater in functional status measurements and ra- to lead to an increase of American Col- the tabalumab group than in the place diographic changes (36). Particularly lege Rheumatology (ACR)20 responses one at weeks 6 and 9, but not at week the ORAL Scan and Step, performed in at week 24. The efficacy was greater in 12. However patients treated with ta- the year 2013, evaluated the reduction patients that presented a high disease balumab showed a significant higher re- of radiological progression and the ef- activity, positive rheumatoid factor duction of DAS28-CRP from baseline ficacy of the compound, respectively, and that did not have anti-TNF treat- at week 6, 9, 12 and 16 when compared in a cohort of patients with failure to ment and also in these patients in which with patients receiving placebo. In this TNF inhibitor (TNFi). The study of Van MTX failed. However, no significantly study was indicated that the reduction der Heijde et al. is a 24-month, double- improvement of ACR50 and ACR70n in efficacy after week 9 might be caused blind trial. This study evaluated the was demonstrated in patients treated by a notable decline in tabalumab con- reduction of structural damage (as the with belimumab in the single Phase II centrations. The study suggested that mean change from baseline in modi- clinical Trial (41). the safety of tabalumab was similar to fied Total Sharp Score – mTSS) in 797 other biologic drugs in RA. patients with active RA non-responder Tabalumab to MTX. A statistically significant dif- Tabalumab is a fully human IgG4 mon- Tofacitinib and other Janus Kinase ference was observed only in the group oclonal antibody that neutralises the (JAK) inhibitors who received the higher dosage of to- two forms of BAFF, the soluble and Novel approaches have focused on the facitinib (10 mg bid) (33). the membrane-bound one. A phase II, development of molecules that inhibit In the ORAL Step, Burmester et al. randomised, placebo-controlled trial in- the JAK/STAT pathway. demonstrated the efficacy of tofaci-

106 Novelties in the treatment of RA / G. Guidelli et al. REVIEW tinib in 400 patients with moderate to of RA Tofacitinib is recommended, evaluated the possible role of mesen- severe RA and inadequate response or where licensed, after the failure of at chymal stromal cells (MSC) for RA pa- intolerance to TNFi. The study is a ran- least one bDMARD. (40). To extend the tients refractory to conventional thera- domised, controlled, 6 months phase use of this drug also after MTX or oth- pies. Wang et al. demonstrated that 136 III study. At month 3 ACR20 response er cDMARD failure more safety data patients with active RA receiving 40 rates were 41.7% for Tofacitinib 5 mg from registries, clinical experience and million allogeneic umbilical cord de- bid and 48.1% for Tofacitinib 10 mg long term studies are needed. In fact, rived MSC had a significant remission bid versus 24.4% for placebo (p=0.0001 data currently available, underline more as ACR improvement, DAS28, HAQ and p<0.05, respectively). The same re- incidence of serious infections under and also a serum levels reduction of sults were both for ACR50 (28% for to- treatment with tofacitinib (particularly inflammatory cytokines such as TNF- facitinib 10 mg bid, 27% for tofacitinib TB and Herpes Zoster) and the pres- alpha and IL6 compared to 36 patients 5 mg bid compared with 8% for placebo ence of changes in laboratory param- treated with placebo (42). The second p<0.0001) and for DAS28-defined re- eters (neutropenia, anaemia, increase in study, presented at the ACR congress in mission (7% for tofacitinib 10 mg bid, serum levels of creatine phosphokinase, 2013, showed in 53 RA patients that the 11% for tofacitinib 5 mg bid compared creatinine and dose-related increase in infusion with allogeneic adipose-de- with 2% for placebo; p<0.05) (34). lipid levels – both LDL and HDL) (40). rived MSC was safe in a dose of 3x1–4 Finally, the ORAL Start Investigators There are also other oral JAK inhibitor million cells per kg when given at day published the last June the results of molecules: Baricitinib (LY3009104) 1, 8 and 15 with rescue therapy allowed a 24 months phase III trial that com- with selectivity for JAK1 e JAK2 that at month 3 and 6. Only one patient had pared tofacitinb in monotherapy to is currently in Phase III clinical devel- a serious adverse event (43). MTX in patients MTX naïve or treated opment; GLPG0634 that inhibits JAK1 with MTX at a non-therapeutic dose. and VX-509 with selectivity for JAK3 References These data demonstrated that Tofaci- that are now investigated in Phase II. 1. HETLAND ML, JENSEN DV, KROGH NS: Mon- itoring patients with rheumatoid arthritis in tinib monotherapy (at dose of 5 or 10 (www.clinicaltrials.gov) routine care: experiences from a treat-to-tar- mg twice daily) was superior to MTX get strategy using the DANBIO registry. Clin in reduction of radiological damage Fostamatinib Exp Rheumatol 2014; 32 (Suppl. 85): S141-6. progression, in clinical outcomes (i.e. Another promising drug for the treat- 2. CHIU YM, LAI MS, LIN HY et al.: Disease ac- tivity affects all domains of quality of life in ACR 20-ACR 50-ACR70 response; ment of patients with rheumatoid ar- patients with rheumatoid arthritis and is mod- DAS 28) and patient-reported out- thritis non-responding to conventional ified by disease duration.Clin Exp Rheumatol comes (i.e. HAQ-DI; FACIT-fatigue). DMARDs or TNF is Fostamatinb. It is a 2014; 32: 898-903. 3. LÓPEZ-GONZÁLEZ R, LEÓN L, LOZA E, RE- Notably, Herpes zoster developed in small molecule, oral spleen Tyrosine Ki- DONDO M, GARCÍA DE YÉBENES MJ, CAR- 4% of patients who received tofaci- nase (Syk) inhibitor. In a phase III study MONA L: Adherence to biologic therapies tinib versus about 1% of patients who of Genovese MC et al. (OSKIRA-3) and associated factors in rheumatoid arthritis, received MTX; moreover, confirmed evaluated the efficacy of this drug in spondyloarthritis and psoriatic arthritis: a sys- tematic literature review. Clin Exp Rheumatol cases of cancer developed in 5 patients patients previous treated with MTX 2015 Jan 20 [Epub ahead of print]. who received tofacitinib and only in and a single TNF-α, was not achieved 4. WU B, SONG Y, LENG L, BUCALA R, LU LJ: one patient who received MTX. In con- an improvement in ACR20 response at Treatment of moderate rheumatoid arthritis with different strategies in a health resource- clusion, these results demonstrated that 24 weeks in the group of patients tak- limited setting: a cost-effectiveness analysis tofacitinib is effective in reducing signs ing fostamatinib 100 mg bid for 4 weeks in the era of biosimilars. Clin Exp Rheumatol and symptoms as well as disease activi- then 150 mg once daily compared to 2015; 33: 20-26. ty and physical function in patients with placebo (41). 5. PITSILKA DA, KAFETSIOS K, NIAKAS D: Social support and quality of life in patients moderate to severe rheumatoid arthritis, In December 2014, Weinblatt et al. with rheumatoid arthritis in Greece. Clin Exp MTX-naive or after treatment failure to published the results of OSKIRA-1, Rheumatol 2015; 33: 27-33. non-biologic and biologic DMARDs. a phase III clinical trial that compared 6. SMOLEN JS, LANDEWÉ R, BREEDVELD FC et al.: EULAR recommendations for the man- In November 2012 the Food and Drug fostamatinib at two different dosages agement of rheumatoid arthritis with synthetic Administration (FDA) approved Tofac- (100 mg twice daily and 150 mg once and biological disease-modifying antirheu- itinib at the dosage of 5 mg bid for the daily, respectively) with placebo. It was matic drugs. Ann Rheum Dis 2010; 69: 964- treatment of moderate to severe RA in demonstrated an improvement in the 75. 7. KITAHAMA M, NAKAJIMA A, INOUE E, TANI- patients who have had intolerance or in- ACR20 response in patients MTX non- GUCHI A, MOMOHARA S, YAMANAKA H: adequate response to MTX. Tofacitinib responders treated with Fostamatinib at Efficacy of adjunct tacrolimus treatment in can be used as monotherapy or in com- 24 weeks compared to placebo but there patients with rheumatoid arthritis with inad- equate responses to methotrexate. Mod Rheu- bination with MTX or other non-bio- was not reported a significant difference matol 2013; 23: 788-93. logic DMARDs. It cannot be used with in the modified total Sharp/van der Hei- 8. TANAKA Y, KAWAI S, TAKEUCHI T, YAMAMO- biological DMARDs or potent immu- jde score of radiographic damage (38). TO K, MIYASAKA N: Prevention of joint de- struction by tacrolimus in patients with early nosuppressives such as azathioprine or rheumatoid arthritis: a post hoc analysis of a cyclosporine. In the last 2013 EULAR Mesenchimal stromal cells double-blind, randomized, placebo-controlled recommendations for the management In the last two years, two large studies study. Mod Rheumatol 2013; 23: 1045-52.

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TANAKA Y, MARTIN MOLA E: IL-6 targeting JAK inhibitor tofacitinib (CP-690,550) ver- refractory rheumatoid arthritis patients. In: compared to TNF targeting in rheumatoid sus placebo in combination with background Abstract at the Annual Scientific Meeting arthritis: studies of olokizumab, sarilumab methotrexate in patients with active rheuma- ACR; 2013.

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